TY  - JOUR
AB  - Recently, interest for the potential impact of consumer-relevant engineered nanoparticles on pregnancy has dramatically increased. This study investigates whether inhaled silver nanoparticles (AgNPs) reach and cross mouse placental barrier and induce adverse effects. Apart from their relevance for the growing use in consumer products and biomedical applications, AgNPs are selected since they can be unequivocally identified in tissues. Pregnant mouse females are exposed during the first 15 days of gestation by nose-only inhalation to a freshly produced aerosol of 18-20 nm AgNPs for either 1 or 4 hours, at a particle number concentration of 3.80 × 107 part. cm(-3) and at a mass concentration of 640 µg/m³. AgNPs are identified and quantitated in maternal tissues, placentas and foetuses by Transmission Electron Microscopy coupled with Energy-dispersive X-ray spectroscopy and single-particle Inductively Coupled Plasma Mass Spectrometry. Inhalation of AgNPs results in increased number of resorbed foetuses, associated to reduced oestrogen plasma levels, in the 4h/day exposed mothers. Increased expression of pregnancy-relevant inflammatory cytokines is also detected in the placentas of both groups. These results proof that NPs are able to reach and cross the mouse placenta, and suggest that precaution should be taken with respect to acute exposure to nanoparticles during pregnancy.
AU  - Campagnolo, L.*
AU  - Massimiani, M.*
AU  - Vecchione, L.*
AU  - Piccirilli, D.*
AU  - Toschi, N.*
AU  - Magrini, A.*
AU  - Bonanno, E.*
AU  - Scimeca, M.*
AU  - Castagnozzi, L.*
AU  - Buonanno, G.*
AU  - Stabile, L.*
AU  - Cubadda, F.*
AU  - Aureli, F.*
AU  - Fokkens, P.H.*
AU  - Kreyling, W.G.
AU  - Cassee, F.R.*
AU  - Pietroiusti, A.*
C1  - 51358
C2  - 43197
CY  - Abingdon
SP  - 687-698
TI  - Silver nanoparticles inhaled during pregnancy reach and affect the placenta and the foetus.
JO  - Nanotox.
VL  - 11
IS  - 5
PB  - Taylor & Francis Ltd
PY  - 2017
SN  - 1743-5390
ER  - 

TY  - JOUR
AB  - The biokinetics of a size-selected fraction (70nm median size) of commercially available and (48)V-radiolabeled [(48)V]TiO2 nanoparticles has been investigated in healthy adult female Wistar-Kyoto rats at retention time-points of 1h, 4h, 24h, 7d and 28d after intratracheal instillation of a single dose of an aqueous [(48)V]TiO2-nanoparticle suspension. A completely balanced quantitative biodistribution in all organs and tissues was obtained by applying typical [(48)V]TiO2-nanoparticle doses in the range of 40-240 μg·kg(-1) bodyweight and making use of the high sensitivity of the radiotracer technique. The [(48)V]TiO2-nanoparticle content was corrected for residual blood retained in organs and tissues after exsanguination and for (48)V-ions not bound to TiO2-nanoparticles. About 4% of the initial peripheral lung dose passed through the air-blood-barrier after 1h and were retained mainly in the carcass (4%); 0.3% after 28d. Highest organ fractions of [(48)V]TiO2-nanoparticles present in liver and kidneys remained constant (0.03%). [(48)V]TiO2-nanoparticles which entered across the gut epithelium following fast and long-term clearance from the lungs via larynx increased from 5-20% of all translocated/absorbed [(48)V]TiO2-nanoparticles. This contribution may account for 1/5 of the nanoparticle retention in some organs. After normalizing the fractions of retained [(48)V]TiO2-nanoparticles to the fraction that reached systemic circulation, the biodistribution was compared with the biodistributions determined after IV-injection (Part-1) and gavage (Part-2). The biokinetics patterns after IT-instillation and gavage were similar but both were distinctly different from the pattern after intravenous injection disproving the latter to be a suitable surrogate of the former applications. Considering that chronic occupational inhalation of relatively biopersistent TiO2-particles (including nanoparticles) and accumulation in secondary organs may pose long-term health risks, this issue should be scrutinized more comprehensively.
AU  - Kreyling, W.G.
AU  - Holzwarth, U.*
AU  - Haberl, N.
AU  - Kozempel, J.*
AU  - Wenk, A.
AU  - Hirn, S.
AU  - Schleh, C.
AU  - Schäffler, M.
AU  - Lipka, J.
AU  - Semmler-Behnke, M.
AU  - Gibson, N.*
C1  - 50719
C2  - 42857
CY  - Abingdon
SP  - 454-464
TI  - Quantitative biokinetics of titanium dioxide nanoparticles after intratracheal instillation in rats (Part 3).
JO  - Nanotox.
VL  - 11
IS  - 4
PB  - Taylor & Francis Ltd
PY  - 2017
SN  - 1743-5390
ER  - 

TY  - JOUR
AB  - The biokinetics of a size-selected fraction (70nm median size) of commercially available and (48)V-radiolabeled [(48)V]TiO2 nanoparticles has been investigated in female Wistar-Kyoto rats at retention timepoints 1h, 4h, 24h and 7days after oral application of a single dose of an aqueous [(48)V]TiO2-nanoparticle suspension by intra-esophageal instillation. A completely balanced quantitative body clearance and biokinetics in all organs and tissues was obtained by applying typical [(48)V]TiO2-nanoparticle doses in the range of 30-80 μg•kg(-1) bodyweight, making use of the high sensitivity of the radiotracer technique. The [(48)V]TiO2-nanoparticle content was corrected for nanoparticles in the residual blood retained in organs and tissue after exsanguination and for (48)V-ions not bound to TiO2-nanoparticles. Beyond predominant fecal excretion about 0.6% of the administered dose passed the gastro-intestinal-barrier after -h and about 0.05% were still distributed in the body at day-7, with quantifiable [(48)V]TiO2-nanoparticle organ concentrations present in liver (0.09ng•g(-1)), lungs (0.10ng•g(-1)), kidneys (0.29ng•g(-1)), brain (0.36ng•g(-1)), spleen (0.45ng•g(-1)), uterus (0.55ng•g(-1)) and skeleton (0.98ng•g(-1)). Since chronic, oral uptake of TiO2 particles (including a nano-fraction) by consumers has continuously increased in the past decades, the possibility of chronic accumulation of such biopersistent nanoparticles in secondary organs and the skeleton raises questions about the responsiveness of their defense capacities, and whether these could be leading to adverse health effects in the population at large. After normalizing the fractions of retained [(48)V]TiO2-nanoparticles to the fraction that passed the gastro-intestinal-barrier and reached systemic circulation the biokinetics was compared to the biokinetics determined after IV-injection (Part 1). Since the biokinetics patterns differ largely IV-injection is not an adequate surrogate for assessing the biokinetics after oral exposure to TiO2 nanoparticles.
AU  - Kreyling, W.G.
AU  - Holzwarth, U.*
AU  - Schleh, C.
AU  - Kozempel, J.*
AU  - Wenk, A.
AU  - Haberl, N.
AU  - Hirn, S.
AU  - Schäffler, M.
AU  - Lipka, J.
AU  - Semmler-Behnke, M.
AU  - Gibson, N.*
C1  - 50720
C2  - 42856
CY  - Abingdon
SP  - 443-453
TI  - Quantitative biokinetics of titanium dioxide nanoparticles after oral application in rats (Part 2).
JO  - Nanotox.
VL  - 11
IS  - 4
PB  - Taylor & Francis Ltd
PY  - 2017
SN  - 1743-5390
ER  - 

TY  - JOUR
AB  - Submicrometer TiO2 particles, including nanoparticulate fractions, are used in an increasing variety of consumer products, as food additives and drug delivery applications are envisaged. Beyond exposure of occupational groups this entails an exposure risk to the public. However, nanoparticle translocation from the organ of intake and potential accumulation in secondary organs is poorly understood and in many investigations excessive doses are applied. The present study investigates the biokinetics and clearance of a low single dose (typically 40-400 µg/kg BW) of (48)V-radiolabeled, pure TiO2 anatase nanoparticles ([(48)V]TiO2NP) with a median aggregate/agglomerate size of 70 nm in aqueous suspension after intravenous injection into female Wistar rats. Biokinetics and clearance were followed from 1-hour to 4-weeks. The use of radiolabeled nanoparticles allowed a quantitative [(48)V]TiO2NP balancing of all organs, tissues, carcass and excretions of each rat without having to account for chemical background levels possibly caused by dietary or environmental titanium exposure. Highest [(48)V]TiO2NP accumulations were found in liver (95.5%ID on day-1), followed by spleen (2.5%), carcass (1%), skeleton (0.7%) and blood (0.4%). Detectable nanoparticle levels were found in all other organs. The [(48)V]TiO2NP content in blood decreased rapidly after 24h while the distribution in other organs and tissues remained rather constant until day-28. The present biokinetics study is part 1 of a series of studies comparing biokinetics after three classical routes of intake (intravenous (IV) injection (part 1), ingestion (part 2), intratracheal instillation (part 3)) under identical laboratory conditions, in order to verify the common hypothesis that IV-injection is a suitable predictor for the biokinetics fate of nanoparticles administered by different routes. This hypothesis is disproved by this series of studies.
AU  - Kreyling, W.G.
AU  - Holzwarth, U.*
AU  - Haberl, N.
AU  - Kozempel, J.*
AU  - Hirn, S.
AU  - Wenk, A.
AU  - Schleh, C.
AU  - Schäffler, M.
AU  - Lipka, J.
AU  - Semmler-Behnke, M.
AU  - Gibson, N.*
C1  - 50721
C2  - 42855
CY  - Abingdon
SP  - 434-442
TI  - Quantitative biokinetics of titanium dioxide nanoparticles after intravenous injection in rats (Part 1).
JO  - Nanotox.
VL  - 11
IS  - 4
PB  - Taylor & Francis Ltd
PY  - 2017
SN  - 1743-5390
ER  - 

TY  - JOUR
AB  - It is of urgent need to identify the exact physico-chemical characteristics, which allow maximum uptake and accumulation in secondary target organs of nanoparticulate drug delivery systems after oral ingestion. We administered radio labelled gold nanoparticles in different sizes (1.4 - 200nm) with negative surface charge and 2.8nm nanoparticles with opposite surface charges by intra-oesophageal instillation into healthy adult female rats. The quantitative amount of the particles in organs, tissues and excrements was measured after 24 hours by gamma-spectroscopy. The highest accumulation in secondary organs was mostly found for 1.4nm particles; the negatively charged particles were accumulated mostly more than positively charged particles. Importantly, 18nm particles show a higher accumulation in brain and heart compared to other sized particles. No general rule accumulation can be made so far. Therefore, specialised drug delivery systems via the oral route have to be individually designed, depending on the respective target organ.
AU  - Schleh, C.
AU  - Semmler-Behnke, M.
AU  - Lipka, J.
AU  - Wenk, A.
AU  - Hirn, S.
AU  - Schäffler, M.
AU  - Schmid, G.*
AU  - Simon, U.*
AU  - Kreyling, W.G.
C1  - 2646
C2  - 27752
SP  - 36-46
TI  - Size and surface charge of gold nanoparticles determine absorption across intestinal barriers and accumulation in secondary target organs after oral administration.
JO  - Nanotox.
VL  - 6
IS  - 1
PY  - 2012
SN  - 1743-5390
ER  - 

TY  - JOUR
AB  - This paper presents the outcomes from a workshop of the European Network on the Health and Environmental Impact of Nanomaterials (NanoImpactNet). During the workshop, 45 experts in the field of safety assessment of engineered nanomaterials addressed the need to systematically study sets of engineered nanomaterials with specific metrics to generate a data set which would allow the establishment of dose-response relations. The group concluded that international cooperation and worldwide standardization of terminology, reference materials and protocols are needed to make progress in establishing lists of essential metrics. High quality data necessitates the development of harmonized study approaches and adequate reporting of data. Priority metrics can only be based on well-characterized dose-response relations derived from the systematic study of the bio-kinetics and bio-interactions of nanomaterials at both organism and (sub)-cellular levels. In addition, increased effort is needed to develop and validate analytical methods to determine these metrics in a complex matrix. Read More: http://informahealthcare.com/doi/abs/10.3109/17435391003775266
AU  - Bouwmeester, H.*
AU  - Lynch, I.*
AU  - Marvin, H.J.P.*
AU  - Dawson, K.A.*
AU  - Berges, M.*
AU  - Braguer, D.*
AU  - Byrne, H.J.*
AU  - Casey, A.*
AU  - Chambers, G.*
AU  - Clift, M.J.D.*
AU  - Elia, G.*
AU  - Fernandes, T.F.*
AU  - Fjellsbo, L.B.*
AU  - Hatto, P.*
AU  - Juillerat, L.*
AU  - Klein, C.*
AU  - Kreyling, W.G.
AU  - Nickel, C.*
AU  - Riediker, M.*
AU  - Stone, V.*
C1  - 5284
C2  - 27745
SP  - 1-11
TI  - Minimal analytical characterization of engineered nanomaterials needed for hazard assessment in biological matrices.
JO  - Nanotox.
VL  - 5
IS  - 1
PB  - Informa Plc.
PY  - 2011
SN  - 1743-5390
ER  - 

TY  - JOUR
AB  - One of the most urgent requirements in nanotoxicology is a quantitative assessment of internalized nanomaterials in cells. We present an in vitro assay called 'max-flat' for the measurement of internalized particles in macrophages. Fluorescent polystyrene (PS) beads of diameters 1µm, 500 nm, 200 nm, 100 nm and 20 nm were employded. Different concentrations of fibronectin (FN) coated substrates were tested to achieve a maximal cell spreading area and minimal nucleus height, hence 'max-flat'. We found the cell spreading area depends on FN concentration, and it is independent of particle concentration. An optimal conditon of FN was found at 2.5 x 10-3 mg/ml, and it was selected for the max-flat assay to assess the internalization of PS beads. Cells under these conditions neither generate reactive oxygen species nor show noticeable differences in pro-survival/pro-apoptotic signals. Confocal images were employed for the max-flat assay and we set the interval scanning for a Z-stack as nucleus height divided by particle diameter. The max-flat assay provided a significantly higher number of internalized particles and the saturation is reached faster for nano-scale PS beads. We show how the proposed max-flat assay clearly outperform existing techniques by providing easier, more precise and far more reliable access to the number of internalized nanoparticles in macrophages.
AU  - Tian, F.
AU  - Prina-Mello, A.*
AU  - Estrada, G.
AU  - Beyerle, A.
AU  - Möller, W.
AU  - Schulz, S.
AU  - Kreyling, W.G.
AU  - Stöger, T.
C1  - 1846
C2  - 25960
SP  - 232-242
TI  - A novel assay for the quantification of internalized nanoparticles in macrophages.
JO  - Nanotox.
VL  - 2
IS  - 4
PB  - Taylor & Francis
PY  - 2008
SN  - 1743-5390
ER  -